Method of molding a microneedle

ABSTRACT

A method of molding a microneedle using a mold apparatus that comprises a mold insert ( 210 )having the negative image of at least one microneedle ( 12 ), a compression core ( 240 ), and a mold housing configured to allow a reciprocal motion between the mold insert and the compression core. The mold apparatus has an open position and a closed position. The mold apparatus is placed in the closed position and polymeric material is injected into the closed mold apparatus. The injected polymeric material is compressed between the mold insert and the compression core by a reciprocal motion between the compression core and the mold insert. Also, molding methods wherein the mold apparatus has sidewalls having an injection gate ( 270 ). Also, molding methods comprising a heated mold insert. Also, molding methods comprising the application of high frequency acoustic energy, such as ultrasonic energy, to the mold apparatus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. 371 ofPCT/US2005/044121, filed Dec. 7, 2005, which claims priority to60/634,319, filed Dec. 7, 2004, the disclosure of which is incorporatedby reference in its/their entirety herein.

FIELD

The present invention relates to methods of molding microneedles. In oneaspect, the present invention relates to methods of molding microneedlearrays.

BACKGROUND

Only a limited number of molecules with demonstrated therapeutic valuecan be transported through the skin, even with the use of approvedchemical enhancers. The main barrier to transport of molecules throughthe skin is the stratum corneum (the outermost layer of the skin).

Devices including arrays of relatively small structures, sometimesreferred to as microneedles or micro-pins, have been disclosed for usein connection with the delivery of therapeutic agents and othersubstances through the skin and other surfaces. The devices aretypically pressed against the skin in order to pierce the stratumcorneum such that the therapeutic agents and other substances can passthrough that layer and into the tissues below.

Molding processes to prepare microneedles and microneedle arrays havebeen previously disclosed, but microneedles are very fine structuresthat can be difficult to prepare in a polymeric molding process and theknown microneedle molding processes all have certain disadvantages.

SUMMARY OF THE INVENTION

The present invention provides, among other things, an improved moldingprocess for preparing microneedle arrays comprising a combination ofinjection and compression molding processes. The ability to reproducethe mold shape in the final molded part, reliably produce microneedlesof a consistent height, and produce microneedle arrays in an economicalfashion are among the desirable features of this invention. In oneembodiment, this invention is particularly suitable for moldingmicroneedles made from tough engineering grade plastics.

In one embodiment, the present invention is a method of molding amicroneedle using a mold apparatus that comprises a mold insert havingthe negative image of at least one microneedle, a compression core,sidewalls having an injection gate, and a mold housing configured toallow a reciprocal motion between the mold insert and the compressioncore. The mold apparatus has an open position and a closed position. Themold apparatus is placed in the closed position and polymeric materialis injected through the injection gate into the closed mold apparatus.The injected polymeric material is compressed between the mold insertand the compression core by a reciprocal motion between the compressioncore and the mold insert. The mold is opened and a molded microneedle isremoved from the mold.

In another embodiment, the present invention is a method of molding amicroneedle using a mold apparatus that comprises a mold insert havingthe negative image of at least one microneedle, a compression core, anda mold housing configured to allow a reciprocal motion between the moldinsert and the compression core. The mold apparatus has an open positionand a closed position. The mold insert is heated to a temperature ofgreater than or equal to 200° F. (93.3° C.). The mold apparatus isplaced in the closed position and polymeric material is injected intothe closed mold apparatus. The injected polymeric material is compressedbetween the mold insert and the compression core by a reciprocal motionbetween the compression core and the mold insert. The mold is opened anda molded microneedle is removed from the mold.

In another embodiment, the present invention is a method of molding amicroneedle using a mold apparatus that comprises a mold insert havingthe negative image of at least one microneedle, a compression core, anda mold housing configured to allow a reciprocal motion between the moldinsert and the compression core. The mold apparatus has an open positionand a closed position. The mold apparatus is placed in the closedposition and polymeric material is injected into the closed moldapparatus. The polymeric material is characterized by a melt-flow indexgreater than about 5 g/10 minutes when measured by ASTM D1238 atconditions of 300° C. and 1.2 kg weight. The injected polymeric materialis compressed between the mold insert and the compression core by areciprocal motion between the compression core and the mold insert sothat the negative image of the at least one microneedle is substantiallycompletely filled with the injected polymeric material. The mold isopened and a molded microneedle is removed from the mold.

In another embodiment, the present invention is a method of molding amicroneedle using a mold apparatus that comprises a mold insert havingthe negative image of at least one microneedle. The mold apparatus hasan open position and a closed position. Acoustic energy having afrequency greater than about 5,000 Hz is applied to the mold apparatus.The mold apparatus is placed in the closed position and polymericmaterial is injected into the closed mold apparatus. The mold is openedand a molded microneedle is removed from the mold. In one embodiment,the acoustic energy is ultrasonic energy.

In another embodiment, the present invention is a method of molding amicroneedle using a mold apparatus that comprises a mold insert havingthe negative image of at least one microneedle, a compression core, anda mold housing configured to allow a reciprocal motion between the moldinsert and the compression core. The mold apparatus has an open positionand a closed position. The mold apparatus is placed in the closedposition and polymeric material is injected into the closed moldapparatus. The injected polymeric material is compressed between themold insert and the compression core by a reciprocal motion between thecompression core and the mold insert. The mold is opened and a moldedmicroneedle is removed from the mold.

The invention will be further understood by those skilled in the artupon consideration of the remainder of the disclosure, including theDetailed Description and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention will now be described in greaterdetail below with reference to the attached drawings, wherein:

FIG. 1 is a schematic cross-sectional view of one embodiment of a moldapparatus in an open position.

FIG. 2 is a schematic cross-sectional view of one embodiment of a moldapparatus in a closed position.

FIG. 3 is a schematic cross-sectional view of one embodiment of a moldapparatus in a compressed position.

FIG. 4 is a schematic cross-sectional view of one embodiment of a moldapparatus in an open position with an ejected part.

FIG. 5A is a schematic cross-sectional view of a detailed view of oneembodiment of a mold apparatus.

FIG. 5B is a schematic cross-sectional side view of polymeric materialinside the detailed portion of the mold apparatus shown in FIG. 5A.

FIG. 6 is a schematic perspective view of a microneedle array.

FIG. 7 is a microphotograph of a microneedle array.

FIG. 8 is a schematic cross-sectional view of another embodiment of amold apparatus.

FIG. 9A is a schematic cross-sectional view of still another embodimentof a mold apparatus.

FIG. 9B is a side view of a portion of the mold apparatus shown in FIG.9A.

FIG. 10 is a schematic cross-sectional view of still another embodimentof a mold apparatus.

FIG. 11A is a schematic cross-sectional view of still another embodimentof a mold apparatus.

FIG. 11B is a side view of a portion of the mold apparatus shown in FIG.11A.

DETAILED DESCRIPTION

One embodiment of the method of molding a microneedle is shown in FIGS.1 to 4. FIG. 1 shows a mold apparatus in the open position. The moldapparatus comprises a mold housing formed from a first mold member 220and a second mold member 230. The first mold member 220 partiallysurrounds a mold insert 210 which has the negative image of at least onemicroneedle. In the illustrated embodiment, the mold insert 210 has thenegative image of a microneedle array. The second mold member 230partially surrounds a compression core 240, which is conventionally inthe form of a piston. The mold housing is configured to allow areciprocal motion between the mold insert 210 and the compression core240. A wedge 250 that is driven by a hydraulic cylinder 260 transmitsforce to the compression core 240 via a core-wedge connection 245. Theconnection 245 is shown as a separate piece, but may be integrallyformed as part of the compression core 240 or it may be any conventionallinkage that can transmit mechanical force based on the motion of thewedge 250. An input line 280 is used to input molten polymeric materialthrough an injection gate 270 and into the mold cavity that is formedwhen the mold apparatus is in the closed position.

The mold apparatus 200 is shown in the closed position in FIG. 2. Thearrow, identified as “C”, indicates the direction of motion of the rightportion of the apparatus which comprises the second mold member 230,compression core 240, and wedge 250, although it should be noted theorientation of the mold apparatus as shown is arbitrary and may berotated or inverted as desired. The left portion of the mold apparatuscomprises the first mold member 220 and the mold insert 210. In theclosed position, the left and right portions of the apparatus restagainst each other by their joint face, allowing the polymeric materialto be injected into the mold apparatus. The left portion and the rightportion are spaced apart in the open position, making it possible toremove the molded microneedle from the mold.

The mold apparatus 200 in the closed position defines a mold cavity 290.The shape of the mold cavity 290 is defined on one major surface by themold insert 210 and on an opposing major surface by the near end 275 ofthe compression core 240. The second mold member 230 and the mold insert210 also define sidewalls 285. The injection gate 270 is an opening onthe sidewalls 285. In one embodiment, the sidewalls 285 may be formedentirely by the mold insert 210, that is, the near end 275 of thecompression core 240 would be flush with the ends of the second moldmember 230. In another embodiment, the sidewalls 285 may be formedentirely by the second mold member 230, that is, the right hand face ofthe mold insert would be flush with the surface of the first mold member220. It should be understood that the sidewalls 285 may be formed by anycombination of the above descriptions and need not be a separate piece,but are rather intended to define the sides of the mold cavity 290formed by the interrelation of all of the parts of the mold apparatus.Other designs are equally suitable so long as the mold apparatus definesa mold cavity which may be filled with molten polymeric material underpressure.

With the mold apparatus in the closed position, molten polymericmaterial is injected through the input line 280 and injection gate 270to partially fill the mold cavity 290. Once the mold cavity 290 ispartially filled to a desired amount, then the hydraulic cylinder 260moves the wedge 250 in the direction of the arrow identified as ‘A’ inFIG. 3 to place the mold apparatus 200 in a compressed position.Movement of the wedge 250 causes corresponding movement of thecompression core 240 in the direction of the arrow identified as ‘B’,that is, there is a reciprocal motion between the compression core 240and the mold insert 210. The molten polymeric material is thuscompressed within the mold cavity 290 thereby aiding in filling thenegative image of the microneedle array in the mold insert 210. The moldapparatus is subsequently opened, as shown in FIG. 4, and the arrowsshow the direction of motion of the various parts (compression core 240,wedge 250, second mold member 230) returning to their open positions. Amolded microneedle array 295 is then ejected from the open moldapparatus by any conventional method, such as with the use of ejectorpins (not shown). The cycle shown in FIGS. 1 to 4 may subsequently berepeated as desired to produce multiple parts.

In one embodiment the mold apparatus may be configured so as to havemultiple, individual mold cavities. Each mold cavity has a negativeimage of a microneedle array, such that the result of a single cycle ofinjection and compression produces multiple microneedle arrays. Thenumber of individual mold cavities may be, for example, 4 or more, often8 or more, and in some instances 32 or more. The injection pressure withwhich the molten polymeric material is injected into the mold cavitiesmay be adjusted accordingly depending on the shape, size, and number ofcavities being filled. The compressive force to the individual moldcavities may be provided by a single device, such as a hydrauliccylinder, which is configured so as to distribute the compressive forceevenly across the different cavities. Alternatively, more than onedevice may be used to supply compressive force. For example, a hydrauliccylinder may be provided to supply compressive force to each moldcavity, to every two mold cavities, or to every 4 mold cavities.

In one embodiment the mold insert 210 is heated to a temperature ofgreater than or equal to about 200° F. (93.3° C.), and sometimes to atemperature greater than or equal to 250° F. (121° C.). Heating of themold insert may be desirable to aid in flow of the injected polymericmaterial into the fine structures of the mold insert. In particular,heating of the mold insert may allow for use of reduced compressiveforces and/or may decrease cycle times. In a preferred embodiment, thetemperature of the mold insert 210 is held substantially constant. Themold insert is preferably maintained at or below the temperature atwhich the polymeric material will form a part with sufficient rigidityto allow the part to be detached from the mold and handled withoutsignificant distortion or warping occurring. This allows for easierfilling of the mold insert while avoiding a separate cooling step priorto removal of the part. Heating of the mold insert can be accomplishedby any known conventional means, for example, by indirectly heatinganother part of the mold apparatus, such as the first mold member, andallowing the heat to transfer to the mold insert.

In another embodiment, the temperature of the mold insert 210 may becycled so that it is at a higher temperature during the filling part ofthe cycle and at a lower temperature when the part is ejected. Thisso-called ‘thermocycling’ process may aid in filling and removal of thepart. Additional details on thermocycling molding may be found in U.S.Patent Application Ser. No. 60/546,780 and U.S. Pat. No. 5,376,317 (Mauset al.), the disclosures of which are herein incorporated by reference.

In one embodiment, the mold apparatus includes an overflow vent 400connected to the mold cavity 290, as shown in FIG. 5A. Molten polymericmaterial fed through the input line 280 passes through the injectiongate 270 and into the mold cavity 290. The arrow shows the generaldirection of flow of polymeric material from the input line 280 into themold cavity 290. As the polymeric material fills the mold cavity itdisplaces air that was in the cavity. In one embodiment, little or nodisplaced air becomes trapped in pockets within the mold cavity orwithin the negative images of microneedles in the mold insert.

The overflow vent 400 serves as an exit gate to allow displaced air toleave the cavity thus allowing for more uniform filling of the moldcavity with polymeric material. The overflow vent may be positionedanywhere on the outer surface of the mold cavity. In one embodiment theoverflow vent is positioned along the sidewalls of the mold cavity. Inthe embodiment shown in FIG. 5A, the overflow vent 400 is positionedalong the sidewall and opposed to the injection gate 270. FIG. 5B showsa detailed side view of polymeric material 282 within the input line280, polymeric material 402 within the overflow vent 400, and polymericmaterial in the form of a microneedle array 295 within the mold cavity290.

A wide variety of polymeric materials may be suitable for use with thepresent invention. In one embodiment, the material is selected so thatit is capable of forming relatively rigid and tough microneedles thatresist bending or breaking when applied to a skin surface. In oneaspect, the polymeric material has a melt-flow index greater than about5 g/10 minutes when measured by ASTM D1238 at conditions of 300° C. and1.2 kg weight. The melt-flow index is often greater than or equal toabout 10 g/10 minutes and sometimes greater than or equal to about 20g/10 minutes. In another embodiment, the tensile elongation at break asmeasured by ASTM D638 (2.0 in/minute) is greater than about 100 percent.In still another embodiment, the impact strength as measured by ASTMD256, “Notched Izod”, (73° F.) is greater than about 5 ft-lb/inches.Examples of suitable materials include polycarbonate, polyetherimide,polyethylene terephthalate, and mixtures thereof. In one embodiment thematerial is polycarbonate.

Although the compressive force is supplied by a wedge in the illustratedembodiment, any known conventional method of applying force may be usedto provide compressive force to the mold cavity. The compression coremay have any suitable shape that forms a major surface of the moldcavity and allows for application of compressive force to the materialin the mold cavity. The compression core may be in the form of a pistonor pin, and desirably the face of the piston or pin is the same diameteras the part to be formed. One skilled in the art would appreciate thatmany conventional methods for applying force may be utilized, such as,for example, using a hydraulic pancake cylinder.

In one embodiment of the present invention, microneedle arrays withmolded microneedles integrally formed with a substrate may be prepared.FIG. 6 shows such a microneedle array 10. A portion of the array 10 isillustrated with microneedles 12 protruding from a microneedle substratesurface 16. The microneedles 12 may be arranged in any desired pattern14 or distributed over the substrate surface 16 randomly. As shown, themicroneedles 12 are arranged in uniformly spaced rows placed in arectangular arrangement. In one embodiment, arrays of the presentinvention have a patient-facing surface area of more than about 0.1 cm²and less than about 20 cm², in some instances, more than about 0.5 cm²and less than about 5 cm². In the embodiment shown in FIG. 6, a portionof the substrate surface 16 is non-patterned. In one embodiment, thenon-patterned surface has an area of more than about 1 percent and lessthan about 75 percent of the total area of the device surface that facesa skin surface of a patient. In one embodiment, the non-patternedsurface has an area of more than about 0.10 square inch (0.65 cm²) toless than about 1 square inch (6.5 cm²). In another embodiment (notshown), the microneedles are disposed over substantially the entiresurface area of the array 10. The thickness of the substrate surface mayvary depending on the desired end use of the microneedle array. In oneembodiment, the substrate surface may be less than 200 mil (0.51 cm) inthickness, often less than 100 mil (0.25 cm) in thickness, and sometimesless than 50 mil (0.13 cm) in thickness. The substrate surface istypically more than 1 mil (25.4 μm) in thickness, often more than 5 mil(127 μm) in thickness, and sometimes more than 10 mil (203 μm) inthickness.

The microneedles are typically less than 1000 microns in height, oftenless than 500 microns in height, and sometimes less than 250 microns inheight. The microneedles are typically more than 20 microns in height,often more than 50 microns in height, and sometimes more than 125microns in height.

The microneedles may be characterized by an aspect ratio. As usedherein, the term “aspect ratio” is the ratio of the height of themicroneedle (above the surface surrounding the base of the microneedle)to the maximum base dimension, that is, the longest straight-linedimension that the base occupies (on the surface occupied by the base ofthe microneedle). In the case of a pyramidal microneedle with arectangular base, the maximum base dimension would be the diagonal lineconnecting opposed corners across the base. Microneedles of the presentinvention typically have an aspect ratio of between about 2:1 to about5:1 and sometimes between about 2.5:1 to about 4:1.

The microneedle arrays prepared by methods of the present invention maycomprise any of a variety of configurations, such as those described inthe following patents and patent applications, the disclosures of whichare herein incorporated by reference. One embodiment for the microneedledevices comprises the structures disclosed in U.S. Patent ApplicationPublication No. 2003/0045837. The disclosed microstructures in theaforementioned patent application are in the form of microneedles havingtapered structures that include at least one channel formed in theoutside surface of each microneedle. The microneedles may have basesthat are elongated in one direction. The channels in microneedles withelongated bases may extend from one of the ends of the elongated basestowards the tips of the microneedles. The channels formed along thesides of the microneedles may optionally be terminated short of the tipsof the microneedles. The microneedle arrays may also include conduitstructures formed on the surface of the substrate on which themicroneedle array is located. The channels in the microneedles may be influid communication with the conduit structures. Another embodiment forthe microneedle devices comprises the structures disclosed in co-pendingU.S. patent application Ser. No. 10/621,620 filed on Jul. 17, 2003 whichdescribes microneedles having a truncated tapered shape and a controlledaspect ratio. Still another embodiment for the microneedle arrayscomprises the structures disclosed in U.S. Pat. No. 6,313,612 (Sherman,et al.) which describes tapered structures having a hollow centralchannel. Still another embodiment for the microneedle arrays comprisesthe structures disclosed in International Publication No. WO 00/74766(Gartstein, et al.) which describes hollow microneedles having at leastone longitudinal blade at the top surface of tip of the microneedle.

Referring to FIG. 7, each of the microneedles 12 includes a base 20 onthe substrate surface 16, with the microneedle terminating above thesubstrate surface in a tip 22. Although the microneedle base 20 shown inFIG. 7 is rectangular in shape, it will be understood that the shape ofthe microneedles 12 and their associated bases 20 may vary with somebases, e.g., being elongated along one or more directions and othersbeing symmetrical in all directions. The base 20 may be formed in anysuitable shape, such as a square, rectangle, or oval. In one embodimentthe base 20 may have an oval shape (i.e., that is elongated along anelongation axis on the substrate surface 16).

One manner in which the microneedles of the present invention may becharacterized is by height 26. The height 26 of the microneedles 12 maybe measured from the substrate surface 16. It may be preferred, forexample, that the base-to-tip height of the microneedles 12 be about 500micrometers or less as measured from the substrate surface 16.Alternatively, it may be preferred that the height 26 of themicroneedles 12 is about 250 micrometers or less as measured from thebase 20 to the tip 22. It may also be preferred that the height ofmolded microneedles is greater than about 90%, and more preferablygreater than about 95%, of the height of the microneedle topography inthe mold insert. The microneedles may deform slightly or elongate uponejection from the mold insert. This condition is most pronounced if themolded material has not cooled below its softening temperature, but maystill occur even after the material is cooled below its softeningtemperature. It is preferred that the height of the molded microneedlesis less than about 115%, and more preferably less than about 105%, ofthe height of the microneedle topography in the mold.

The general shape of the microneedles of the present invention may betapered. For example, the microneedles 12 may have a larger base 20 atthe substrate surface 16 and extend away from the substrate surface 16,tapering to a tip 22. In one embodiment the shape of the microneedles ispyramidal. In another embodiment, the shape of the microneedles isgenerally conical. In one embodiment the microneedles have a defined tipbluntness, such as that described in co-pending and commonly owned U.S.patent application Ser. No. 10/621,620, filed on Jul. 17, 2003 andentitled MICRONEEDLE DEVICES AND MICRONEEDLE DELIVERY APPARATUS, whereinthe microneedles have a flat tip comprising a surface area measured in aplane aligned with the base of about 20 square micrometers or more and100 square micrometers or less. In one embodiment, the surface area ofthe flat tip will be measured as the cross-sectional area measured in aplane aligned with the base, the plane being located at a distance of0.98 h from the base, where h is the height of the microneedle above thesubstrate surface measured from base to tip.

The motion of the compression core 240 in FIGS. 2 and 3 is shown in anexaggerated fashion for purposes of illustration. In one embodiment, thebulk of the mold cavity 290 is substantially filled prior to compressionand the compression step is performed largely to fill the negativeimages of microneedles 12 in the mold insert 210. The motion of thecompression core is generally selected so as to displace a volumesimilar in size or larger than the volume of the mold cavity thatremains unfilled by the initial injection step. In particular, it may bedesirable to displace a larger volume in order to compensate forshrinkage of polymeric material in the mold cavity. Displacement of alarger volume may also be desirable in order to account for materialthat escapes the mold cavity as parting line flash or to account formold plate deflections. The motion of the compression core and theresulting volume displaced may be adjusted depending on a number ofparameters, including the size of the mold cavity, the shape and numberof features in the mold cavity, the amount of the mold cavity filled bythe initial injection step, and the type of material molded. Since themicroneedle image(s) in the mold insert is relatively small both inheight and volume, the motion of the compression core, that is thecompression stroke, is typically between about 0.001 to 0.010 inches (25μm to 250 μm), often between 0.002 to 0.008 inches (50 μm to 200 μm),and sometimes between 0.003 to 0.006 inches (75 μm to 150 μm).

The applied compressive force is typically greater than 5000 psi (34500kPa), sometimes greater than 30000 psi (207000 kPa), and often greaterthan 60000 psi (414000 kPa). Additional details regardinginjection-compression molding may be found in U.S. Pat. No. 4,489,033(Uda et al.), U.S. Pat. No. 4,515,543 (Hamner), and U.S. Pat. No.6,248,281 (Abe et al.), the disclosures of which are herein incorporatedby reference.

In one embodiment, the negative image(s) of the at least one microneedleis substantially completely filled with injected polymeric materialprior to opening the mold and ejecting the part. By substantiallycompletely filled, it should be understood that the molded microneedleshould have a height greater than about 90 percent of the correspondingheight of the microneedle topography in the mold insert. In oneembodiment, the molded microneedle has a height greater than about 95percent of the corresponding height of the microneedle topography in themold insert. It is preferable that the molded microneedle has a heightsubstantially the same (e.g., 95 percent to 105 percent) as thecorresponding height of the microneedle topography in the mold insert.

Mold inserts suitable for use in the present invention may be made byany known conventional method. In one method, a positive ‘master’ isused to form the mold insert. The positive master is made by forming amaterial into a shape in which the microneedle array will be molded.This master can be machined from materials that include, but are notlimited to, copper, steel, aluminum, brass, and other heavy metals. Themaster can also be made from thermoplastic or thermoset polymers thatare compression formed using silicone molds. The master is fabricated todirectly replicate the microneedle array that is desired. The positivemaster may be prepared by a number of methods and may have microneedlesof any of a variety of shapes, for example, pyramids, cones, or pins.The protrusions of the positive master are sized and spacedappropriately, such that the microneedle arrays formed during moldingusing the subsequently formed mold insert have substantially the sametopography as the positive master.

A positive master may be prepared by direct machining techniques such asdiamond turning, disclosed in U.S. Pat. No. 5,152,917 (Pieper, et al.)and U.S. Pat. No. 6,076,248 (Hoopman, et al.), the disclosures of whichare herein incorporated by reference. A microneedle array can be formedin a metal surface, for example, by use of a diamond turning machine,from which is produced a mold insert having an array of cavity shapes.The metal positive master can be manufactured by diamond turning toleave the desired shapes in a metal surface which is amenable to diamondturning, such as aluminum, copper or bronze, and then nickel plating thegrooved surface to provide the metal master. A mold insert made of metalcan be fabricated from the positive master by electroforming. Thesetechniques are further described in U.S. Pat. No. 6,021,559 (Smith), thedisclosure of which is herein incorporated by reference.

In another embodiment, the present invention comprises a method ofmolding microneedles whereby high frequency acoustic energy, such asultrasonic energy, is applied to the mold apparatus 200. High frequencyacoustic energy, such as ultrasonic energy, is applied to aid inpreventing the injected polymer material from hardening against the faceof the mold insert before cavity pressure and compression stroke forcesthe material into the mold cavity. In one embodiment, ultrasonic energyis applied to the mold insert 210 or input line in conjunction with thecombination of injection and compression molding, for example, asillustrated in FIGS. 1 to 4. In one embodiment, the use of ultrasonicenergy prevents the polymeric material from substantially cooling beforefilling the narrow channels, since the polymeric material can be proneto “skin over” or solidify in the channel prior to complete filling andthus block further flow of molten material. The compressive force usedin conjunction with ultrasonic energy is typically greater than 2000 psi(13800 kPa), often greater than 5000 psi (34500 kPa), and sometimesgreater than 10000 psi (69000 kPa).

Referring to FIG. 8, an ultrasonic horn 802 may be placed up against oneside of the mold insert 810. The first mold member 820 supports the horn802, the mold insert 810 and the input line 880. The second mold member830 is used as described above. Ultrasonic energy from the horn 802 maybe applied at any time while the mold apparatus is in the closedposition, such as during the step of injecting polymeric material orduring the step of compressing the injected polymeric material. In oneembodiment, ultrasonic energy is initially applied after the start ofthe step of injecting polymeric material. In one embodiment, ultrasonicenergy is initially applied before the compressing step. The applicationof ultrasonic energy is preferably stopped before the mold apparatus isopened. In one embodiment, the ultrasonic energy may be applied for atime period of about 0.5 to 5 seconds and sometimes for a time period ofabout 0.5 to 2 seconds.

In another embodiment, the ultrasonic horn 902 in FIGS. 9A, B is shownas a flat, cross-shaped member. Ultrasonic boosters 904, 906 are coupledto opposing sides of the ultrasonic horn 902. The mold insert 910 isshown positioned such that it is placed over one “lobe” of thecross-shaped horn. The application of power from the boosters 904, 906causes application of energy in a direction of shear across the face ofthe mold insert 908 as shown by the two-sided arrow labelled E in FIG.9B. As shown, the face of the ultrasonic horn 902 makes a flush contactwith the back surface of the mold insert 910. Alternatively, the moldinsert 910 may be partially or fully recessed into the surface of theultrasonic horn 902 (as is shown in FIG. 10). The remainder of the moldapparatus is operated as described above. The mold apparatus 900 wouldalso have one or more input lines and injection gates (not shown)suitable for introducing polymeric material into the mold cavity that isformed when the apparatus 900 is placed into a closed position.Ultrasonic energy from the horn 902 may be applied during the step ofinjecting polymeric material or during the step of compressing theinjected polymeric material. The application of ultrasonic energy may bestopped before the mold apparatus is opened.

In still another embodiment, the ultrasonic horn 602 may be a flat,cross-shaped member aligned as shown in FIG. 10. The mold insert 670 isshown partially recessed into one surface of the ultrasonic horn 602.The ultrasonic boosters 604, 606 are shown aligned on adjacent sides ofthe ultrasonic horn 602. A converter (not shown) is coupled to booster606 to drive ultrasonic vibration along an axis parallel to the lengthof the microneedle cavities. The remainder of the mold apparatus isoperated as described above. Ultrasonic energy from the horn 602 may beapplied during the step of injecting polymeric material or during thestep of compressing the injected polymeric material. The application ofultrasonic energy may be stopped before the mold apparatus is opened.

In this and the foregoing embodiments, the arrangement of ultrasonicboosters may be varied, for example, by placing boosters against eachlobe of the ultrasonic horn that does not contact the mold insert, or byplacing boosters against other surfaces of the ultrasonic horn. Theultrasonic horn may have any of a number of other conventional shapessuitable for transmitting ultrasonic energy to the mold apparatus. Forexample, a stepped cylinder (as shown in FIG. 8), a stepped bar, or arectangular bar may be used. Ultrasonic energy may be applied in adirection parallel to the plane of the microneedle array, perpendicularto the plane of the microneedle array, or at some other angle withrespect to the microneedle array. In one embodiment, a solid second moldmember 530 (shown in FIG. 11A) may be used to press up against the firstmold member 520, thereby forming a mold cavity along with the moldinsert 510. The ultrasonic horn 502 and boosters 504, 506 are used asdescribed above to facilitate filling of injected polymeric materialinto the mold insert. The mold insert 510 is shown positioned such thatit is placed over one “lobe” of the cross-shaped horn. The first moldmember 520 and second mold member 530 may be optionally configured sothat multiple mold inserts may be held in place against the ultrasonichorn 502. FIG. 11B shows where three optional mold inserts 512 may beplaced against the horn 502. The mold apparatus 500 would also have oneor more input lines and injection gates (not shown) suitable forintroducing polymeric material into the mold cavity that is formed whenthe apparatus 500 is placed into a closed position. Placement of two ormore mold inserts against the ultrasonic horn could be employed in anyof the foregoing embodiments taking into account the size of the moldinserts and the size of the ultrasonic horn. In embodiments where acompression core is employed it may be advantageous to use an individualcompression core in conjunction with each mold insert or alternatively asingle compression core may be sized and gated appropriately tosimultaneously provide compressive force to more than one mold insert.

The ultrasonic energy used may vary in frequency, but is typicallydefined as having a frequency greater than or equal to about 20,000 Hz.Although any ultrasonic frequency may be used, it will typically be lessthan 60,000 Hz, often less than 40,000 Hz, and sometimes less than30,000 Hz. In one embodiment, the frequency is about 20,000 Hz. Althoughthe specific embodiments of FIGS. 8 to 11 described above refer toultrasonic energy, relatively high frequency acoustic energy with afrequency greater than about 5,000 Hz is also suitable to providevibrational energy to aid in filling the narrow channels of the moldinsert. In one embodiment, the acoustic energy has a frequency ofbetween about 10,000 Hz and 60,000 Hz, often between about 15,000 Hz and40,000 Hz.

Ultrasonic energy may be applied using an ultrasonic horn. The amplitudeof motion of the ultrasonic horn is typically less than about 0.005 inch(127 μm) and is often less than about 0.002 inch (51 μm). In oneembodiment, the amplitude of motion of the ultrasonic horn may bebetween about 0.0005 inch (12.7 μm) and 0.0015 inch (38.1 em). Theultrasonic energy is generally supplied by using a power source thatsupplies electrical energy of the desired frequency. Power sources willtypically provide from 500 to 3000 W power. The electrical energy is fedto a converter or transducer which transforms the electrical energy intomechanical energy with the same frequency. The mechanical vibrations arethen amplified or boosted and transmitted by the ultrasonic horn.

The ultrasonic horn is situated with respect to the mold apparatus sothat vibrational energy is transmitted to the mold apparatus. It may bedesirable, for example, for the ultrasonic horn to be in direct contactwith a portion of the mold apparatus, such as the mold insert. Theapparatus may be configured so that the ultrasonic horn is simply heldagainst the mold insert or the ultrasonic horn may be physicallyconnected to the mold insert by any conventional means. In oneembodiment, the ultrasonic horn may be welded or glued directly to themold insert. In another embodiment, the ultrasonic horn may have arecessed opening into which the mold insert can be press-fit.Alternatively, the mold insert can be chilled, thus causing adimensional contraction, placed into a recessed opening in the horn, andthen allowed to warm and expand, thus causing a firm attachment. In oneembodiment, the ultrasonic horn and mold insert may be connected to eachother by an intermediate member. Such an intermediate member isdesirably selected so as to efficiently transfer ultrasonic energy fromthe horn to the mold insert. In another embodiment, the ultrasonic hornmay comprise part or all of the face of the mold opposed to the moldinsert, such that the ultrasonic horn directly contacts the injectedpolymeric material.

In another embodiment, the present invention is a method of molding amicroneedle using a mold apparatus that comprises a mold insert havingthe negative image of at least one microneedle, a compression core, anda mold housing configured to allow a reciprocal motion between the moldinsert and the compression core. The mold apparatus has an open positionand a closed position. The mold apparatus is placed in the closedposition and polymeric material is injected into the closed moldapparatus. The injected polymeric material is compressed between themold insert and the compression core by a reciprocal motion between thecompression core and the mold insert. The mold is opened and a moldedmicroneedle is removed from the mold. The polymeric material is injectedinto the mold apparatus through an injection gate. The injection gatemay be along the sidewalls of the mold cavity (i.e., side gated) or itmay be aligned along a major surface of the mold cavity (i.e., centergated). Examples of suitable injection gates include a hot tip gate, avalve gate, a tab gate, a tunnel gate, a cashew gate, and a cold 3-platepin gate.

Microneedle arrays prepared by methods of the present invention may besuitable for delivering drugs (including any pharmacological agent oragents) through the skin in a variation on transdermal delivery, or tothe skin for intradermal or topical treatment, such as vaccination.

In one aspect, drugs that are of a large molecular weight may bedelivered transdermally. Increasing molecular weight of a drug typicallycauses a decrease in unassisted transdermal delivery. Microneedledevices suitable for use in the present invention have utility for thedelivery of large molecules that are ordinarily difficult to deliver bypassive transdermal delivery. Examples of such large molecules includeproteins, peptides, nucleotide sequences, monoclonal antibodies, DNAvaccines, polysaccharides, such as heparin, and antibiotics, such asceftriaxone.

In another aspect, microneedle arrays prepared by methods of the presentinvention may have utility for enhancing or allowing transdermaldelivery of small molecules that are otherwise difficult or impossibleto deliver by passive transdermal delivery. Examples of such moleculesinclude salt forms; ionic molecules, such as bisphosphonates, preferablysodium alendronate or pamedronate; and molecules with physicochemicalproperties that are not conducive to passive transdermal delivery.

In another aspect, microneedle arrays prepared by methods of the presentinvention may have utility for enhancing delivery of molecules to theskin, such as in dermatological treatments, vaccine delivery, or inenhancing immune response of vaccine adjuvants. In one aspect, the drugmay be applied to the skin (e.g., in the form of a solution that isswabbed on the skin surface or as a cream that is rubbed into the skinsurface) prior to applying the microneedle device.

Microneedle devices may be used for immediate delivery, that is wherethey are applied and immediately removed from the application site, orthey may be left in place for an extended time, which may range from afew minutes to as long as 1 week. In one aspect, an extended time ofdelivery may be from 1 to 30 minutes to allow for more complete deliveryof a drug than can be obtained upon application and immediate removal.In another aspect, an extended time of delivery may be from 4 hours to 1week to provide for a sustained release of drug.

EXAMPLES Example 1

Molded microneedle arrays were prepared using a 55-ton injection moldingpress (Milacon Cincinnati ACT D-Series Injection Molding Press) equippedwith a thermocycling unit (Regoplas 301 DG Thermal Cycling Unit) in anapparatus as generally shown in FIGS. 1 to 4. Polycarbonate pellets(Lexan® HPS1R-1125, GE Plastics, Pittsfield, Mass.) were loaded into areciprocating screw and heated until molten. The negative mold insertwas heated to a temperature (hereafter referred to as the “moldtemperature at injection”) of 340° F. (171.1° C.). The mold insert wasshaped to provide a microneedle array having a substrate in the shape ofa circular disk with an area of 2 cm². The mold insert was partiallypatterned with cavities in the form of the negative image of an array ofmicroneedles (37×37) in a square shape (1 cm²) in the center of thecircular disk. The microneedle cavities were regularly spaced with adistance of 275 microns between the tips of adjacent microneedlecavities in a square-shaped pattern. Individual microneedle cavitieswere pyramidal in shape with a depth of 250 microns and a square openinghaving a side-length of 83.3 μm. The tips were truncated with a flat,square-shaped top having a side-length of 5 μm. The molding cycle wasinitiated by closing the mold chamber, clamping the mold with 55 tons offorce, and injecting a first portion (approx. 50-95% of the part sizevolume) of the total amount of material from the reciprocating screwinto the negative mold insert. The first portion of material wasinjected into the negative mold insert at a fixed velocity (hereafterreferred to as the “injection velocity”) of 0.50 in/sec (1.27 cm/sec).After injecting the first portion of material the process was switchedfrom an injection-driven to a pressure-driven mode by applying a fixedpressure (hereafter referred to as the “pack pressure”) of 12000 psi(81.6 MPa) to force the remainder of the molten material into thenegative mold insert. The pack pressure was applied for a fixed time(hereafter referred to as the “hold time”) of 4 seconds. The piston wasinitially positioned so that the height of the mold chamber (measuredfrom face of the piston to face of the mold insert) was 30 mil (762 μm).Compression was applied by moving the piston a distance of 5 mil (127μm) towards the opposite side of the microneedle cavity in order tocompress the molten material into the microneedle cavities. The packpressure was subsequently released and the negative mold insert wascooled to an ejection temperature (hereafter referred to as the “moldtemperature at ejection”) of 250° F. (121.1° C.). Then the mold chamberwas opened and a microneedle array was ejected. The average microneedleheight thus formed was 250 μm as measured by viewing with astereomicroscope.

Example 2

Microneedle arrays were prepared as in Example 1 with the followingexceptions. The second mold member had a fixed face and thus nocompression step was used (i.e., as shown in FIG. 11A). The moldtemperature at injection and the mold temperature at ejection were both200° F. (93.3° C.), that is, the mold temperature remained constant.Ultrasonic energy was applied to the mold insert as generally shown inFIG. 10. The ultrasonic energy was turned on before application of thepack pressure (approximately 0.5 second after the onset of injection ofmolten material) and was applied for approximately 1.0 second. Thefrequency was 20,000 Hz and the amplitude of motion of the ultrasonichorn was 1.5 mil (38.1 μm). The average microneedle height thus formedwas 240 μm as measured by viewing with a stereomicroscope.

Example 3

Microneedle arrays were prepared as in Example 1 with the followingexceptions. The mold temperature at injection and the mold temperatureat ejection were both 200° F. (93.3° C.), that is, the mold temperatureremained constant. Ultrasonic energy was applied to the mold insert asgenerally shown in FIG. 10. The ultrasonic energy was turned on beforeapplication of the pack pressure (approximately 0.5 second after theonset of injection of molten material) and was applied for approximately1.0 second. The frequency was 20,000 Hz and the amplitude of motion ofthe ultrasonic horn was 1.5 mil (38.1 μm). The average microneedleheight thus formed was 245 μm as measured by viewing with astereomicroscope.

The present invention has been described with reference to severalembodiments thereof. The foregoing detailed description has beenprovided for clarity of understanding only, and no unnecessarylimitations are to be understood therefrom. It will be apparent to thoseskilled in the art that many changes can be made to the describedembodiments without departing from the spirit and scope of theinvention. Thus, the scope of the invention should not be limited to theexact details of the methods and structures described herein, but ratherby the language of the claims that follow.

1. A method of molding a microneedle comprising: (i) providing a moldapparatus comprising: a mold insert having the negative image of atleast one microneedle; a compression core; a mold housing configured toallow a reciprocal motion between the mold insert and the compressioncore; and sidewalls having an injection gate and the polymeric materialis injected through the injection gate into the closed mold apparatus;wherein the mold apparatus has an open position and a closed position;(ii) placing the mold apparatus in the closed position; (iii) heatingthe mold insert to a temperature of greater than or equal to 200° F.(93.3° C.) before the polymeric material is injected through theinjection gate into the closed mold apparatus; (iii) injecting polymericmaterial into the closed mold apparatus; (iv) compressing the injectedpolymeric material between the mold insert and the compression core by areciprocal motion between the compression core and the mold insert; (v)opening the mold; and (vi) removing a molded microneedle from the mold;wherein the mold insert has a mold insert height and the moldedmicroneedle has a height that is from about 90% of the mold insertheight to about 115% of the mold insert height; and wherein the moldinsert has the negative image of a plurality of microneedles in the formof an array comprising a plurality of microneedles integrally formedwith a substrate, and wherein the microneedle array comprises aplurality of microneedles having a substantially flat tip comprising asurface area measured in a plane aligned with the base of about 20square micrometers or more and 100 square micrometers or less.
 2. Amethod as claimed in claim 1 wherein the sidewalls further comprise anoverflow vent.
 3. A method as claimed in claim 1 wherein the negativeimage of the at least one microneedle is substantially completely filledwith injected polymeric material.
 4. A method as claimed in claim 1wherein the injected polymeric material has a melt-flow index greaterthan about 5 g/10 minutes at conditions of 300° C. and 1.2 kg weight. 5.A method as claimed in claim 4 wherein the negative image of the atleast one microneedle is substantially completely filled with theinjected polymeric material during the compressing step.
 6. A method asclaimed in claim 1 wherein a wedge is used to move the compression coretowards the mold insert.
 7. A method as claimed in claim 6 wherein thewedge is moved in a direction orthogonal to the motion of thecompression core.
 8. A method as claimed in claim 1 wherein thecompression core is moved a distance of between 0.002 inches (50.8 μm)to 0.010 inches (254 μm) towards the mold insert.
 9. A method as claimedin claim 1 wherein the polymeric material is selected from the groupconsisting of polycarbonate, polyetherimide, polyethylene terephthalate,and a mixture thereof
 10. A method as claimed in claim 1 wherein thepolymeric material is polycarbonate.
 11. A method as claimed in claim 1wherein the compressive force applied to the mold cavity during thecompressing step is greater than 5000 psi (34500 kPa).
 12. A method asclaimed in claim 1 wherein the mold insert has the negative image of aplurality of arrays.
 13. A method as claimed in claim 1, wherein themicroneedle array is formed as part of a larger array, wherein at leasta portion of the larger array comprises a non-patterned substrate.
 14. Amethod as claimed in claim 13, wherein the non-patterned substrate hasan area of more than about 0.10 square inch (0.65 cm²) and less thanabout 1 square inch (6.5 cm²).
 15. A method as claimed in claim 1,wherein the microneedle array comprises a plurality of microneedleshaving a substantially pyramidal shape.
 16. A method as claimed in claim1 wherein the mold insert is held at a substantially constanttemperature during the injecting, compressing, and opening steps.